Cannabis contains a number of compounds including delta-9-Tetrahydrocannabinol (THC) and cannabidiol (CBD). THC, believed to be responsible for the psychotic effects of cannabis, produces a wide range of psychotomimetic, cognitive and psychophysiological effects in healthy humans that are relevant to schizophrenia. CBD, on the other hand, does not have any propsychotic effects and instead appears to reduce the overall psychotic effects of cannabis. While preclinical data support the antipsychotic potential of CBD in a number of animal models of psychosis, there are significant limitations to evidence from human studies. CBD attenuates a number of THC-induced subjective effects, whether this extends to THC-induced psychotomimetic or cognitive effects is unclear. Aims: The overarching aim of this proposal is to demonstrate that pretreatment with CBD will reduce a wide range of psychotomimetic, cognitive and psychophysiological effects induced by the acute administration of THC in healthy humans. This study is designed as a first proof of concept to explore the antipsychotic potential of CBD in healthy individuals. The data from this study will serve as a prelude to more comprehensive and expensive clinical trials of CBD in patients with schizophrenia. Methods: 20 psychiatrically and medically healthy individuals, who have been exposed to cannabis but have never met criteria for a cannabis use disorder, will be recruited from the community to participate in this randomized, double-blinded, placebo-controlled study. Subjects will be randomized to (A) four test days or (B) six test days. All 20 subjects will complete (A) 4 test days and receive either CBD (5mg) or placebo followed by THC or placebo intravenously. 10 subjects randomized to (B) six test days will participate in 2 extra test days during which they will receive CBD (2.5mg or 7.5mg) followed by THC. Subjects will be tested before and after drug administration for schizophrenia-like symptoms (measured on the positive and negative syndrome scale (PANSS) and clinician administered dissociative symptoms scale (CADSS), cognitive impairments (in verbal memory, spatial working memory and sustained attention), subjective effects (measured on a visual analog scale of mood states for anxiety and euphoria), psychophysiological effects (P300 event related potential) and endocrine effects (serum ACTH, cortisol and prolactin levels). In addition, blood levels of THC, its active and inactive metabolites, and CBD will be measured in each subject to explore pharmacokinetic interactions. Significance: Most pharmacological treatments currently available for schizophrenia involve primarily the dopaminergic and serotonergic systems. There is a need to develop new pharmacotherapies for schizophrenia driven by novel hypotheses. CBD targets the cannabinoid system and may have antipsychotic properties. Thus, exploration of its antipsychotic properties may lead to newer therapeutic options for schizophrenia. PUBLIC HEALTH RELEVANCE: There is a need to develop new medications for the treatment of schizophrenia based on new hypotheses. Cannabidiol (CBD), which produces effects through the brain cannabinoid system, appears to have antipsychotic potential. The aim of this proposal is to test the antipsychotic effects of CBD in humans in a controlled laboratory study.